Pulsatile Gonadotropin-Releasing Hormone Therapy Is Associated With Better Spermatogenic Outcomes than Gonadotropin Therapy in Patients With Pituitary Stalk Interruption Syndrome.

OBJECTIVE: To compare the effects of combined gonadotropin and pulsatile gonadotropin-releasing hormone (GnRH) therapy on spermatogenesis in patients with pituitary stalk interruption syndrome (PSIS). METHODS: Male patients with PSIS (N = 119) were retrospectively studied. Patients received pulsatile GnRH therapy (N = 59) were divided into response and poor-response groups based on luteinizing hormone (LH) levels after 1-month treatment with a cutoff value of 1 or 2 IU/L. Participants with gonadotropin therapy were divided into human menopausal gonadotropin (hMG)/human chorionic gonadotropin (hCG) group (N = 60), and patients with pulsatile GnRH therapy were classified into GnRH group (N = 28) with treatment duration ≥6 months. RESULTS: The overall success rates of spermatogenesis for hMG/hCG and GnRH therapy were 51.67% (31/60) vs 33.90% (20/59), respectively. GnRH group required a shorter period to induce spermatogenesis (8 vs 15 months, P = .019). hMG/hCG group had higher median total testosterone than GnRH group [2.16, interquartile range(IQR) 1.06-4.89 vs 1.31, IQR 0.21-2.26 ng/mL, P = .004]. GnRH therapy had a beneficial effect on spermatogenesis compared to hMG/hCG therapy (hazard ratio 1.97, 95% confidence interval 1.08-3.57, P = .026). In patients with pulsatile GnRH therapy, compared with the poor-response group, the response group had a higher successful spermatogenesis rate (5.00% vs 48.72%, P = .002) and higher median basal total testosterone (0.00, IQR 0.00-0.03 vs 0.04, IQR 0.00-0.16 ng/mL, P = .026) with LH = 1 IU/L as the cutoff value after 1-month pulsatile GnRH therapy. CONCLUSIONS: Pulsatile GnRH therapy was superior to hMG/hCG therapy for spermatogenesis in patients with PSIS. Earlier spermatogenesis and higher concentrations of sperm could be obtained in the GnRH group if patients received therapy over 6 months.

Multi-omics analyses of serum metabolome, gut microbiome and brain function reveal dysregulated microbiota-gut-brain axis in bipolar depression.

The intricate processes of microbiota-gut-brain communication in modulating human cognition and emotion, especially in the context of mood disorders, have remained elusive. Here we performed faecal metagenomic, serum metabolomics and neuroimaging studies on a cohort of 109 unmedicated patients with depressed bipolar disorder (BD) patients and 40 healthy controls (HCs) to characterise the microbial-gut-brain axis in BD. Across over 12,000 measured metabolic features, we observed a large discrepancy (73.54%) in the serum metabolome between BD patients and HCs, spotting differentially abundant microbial-derived neuroactive metabolites including multiple B-vitamins, kynurenic acid, gamma-aminobutyric acid and short-chain fatty acids. These metabolites could be linked to the abundance of gut microbiota presented with corresponding biosynthetic potentials, including Akkermansia muciniphila, Citrobacter spp. (Citrobacter freundii and Citrobacter werkmanii), Phascolarctobacterium spp., Yersinia spp. (Yersinia frederiksenii and Yersinia aleksiciae), Enterobacter spp. (Enterobacter cloacae and Enterobacter kobei) and Flavobacterium spp. Based on functional neuroimaging, BD-related neuroactive microbes and metabolites were discovered as potential markers associated with BD-typical features of functional connectivity of brain networks, hinting at aberrant cognitive function, emotion regulation, and interoception. Our study combines gut microbiota and neuroactive metabolites with brain functional connectivity, thereby revealing potential signalling pathways from the microbiota to the gut and the brain, which may have a role in the pathophysiology of BD.

Three-Dimensional Nanopillar Arrays-Based Efficient and Flexible Perovskite Solar Cells with Enhanced Stability.

Perovskite nanopillars (PNPs) are propitious candidates for solar irradiation harvesting and are potential alternatives to thin films in flexible photovoltaics. To realize efficient daily energy output, photovoltaics must absorb sunlight over a broad range of incident angles and wavelengths congruent with the solar spectrum. Herein, we report highly periodic three-dimensional (3D) PNP-based flexible photovoltaics possessing a core-shell structure. The vertically aligned PNP arrays demonstrate up to 95.70% and 75.10% absorption at peak and under an incident angle of 60°. The efficient absorption and the orthogonal carrier collection facilitate an external quantum efficiency of 84.0%-89.18% for broadband wavelength. PNPs have been successfully implemented in flexible solar cells. The porous alumina membrane protects PNPs against water and oxygen intrusion and thereby imparts robustness to photovoltaic devices. Meanwhile, the excellent tolerance to mechanical stress/strain enables our unique PNP-based device to provide efficient solar-to-electricity conversion while undergoing mechanical bending.

Caloric restriction reduces the pro-inflammatory eicosanoid 20-hydroxyeicosatetraenoic acid to protect from acute kidney injury.

Acute kidney injury is a frequent complication in the clinical setting and associated with significant morbidity and mortality. Preconditioning with short-term caloric restriction is highly protective against kidney injury in rodent ischemia reperfusion injury models. However, the underlying mechanisms are unknown hampering clinical translation. Here, we examined the molecular basis of caloric restriction-mediated protection to elucidate the principles of kidney stress resistance. Analysis of an RNAseq dataset after caloric restriction identified Cyp4a12a, a cytochrome exclusively expressed in male mice, to be strongly downregulated after caloric restriction. Kidney ischemia reperfusion injury robustly induced acute kidney injury in male mice and this damage could be markedly attenuated by pretreatment with caloric restriction. In females, damage was significantly less pronounced and preconditioning with caloric restriction had only little effect. Tissue concentrations of the metabolic product of Cyp4a12a, 20-hydroxyeicosatetraenoic acid (20-HETE), were found to be significantly reduced by caloric restriction. Conversely, intraperitoneal supplementation of 20-HETE in preconditioned males partly abrogated the protective potential of caloric restriction. Interestingly, this effect was accompanied by a partial reversal of caloric restriction--induced changes in protein but not RNA expression pointing towards inflammation, endoplasmic reticulum stress and lipid metabolism. Thus, our findings provide an insight into the mechanisms underlying kidney protection by caloric restriction. Hence, understanding the mediators of preconditioning is an important prerequisite for moving towards translation to the clinical setting.

Reduction of Tet2 exacerbates early stage Alzheimer's pathology and cognitive impairments in 2×Tg-AD mice.

Abnormal modification of 5-hydroxymethylcytosine (5hmC) is closely related to the occurrence of Alzheimer's disease (AD). However, the role of 5hmC and its writers, ten-eleven translocation (Tet) proteins, in regulating the pathogenesis of AD remains largely unknown. We detected a significant decrease in 5hmC and Tet2 levels in the hippocampus of aged APPswe/PSEN1 double-transgenic (2×Tg-AD) mice that coincides with abundant amyloid-ß (Aß) plaque accumulation. On this basis, we examined the reduction of Tet2 expression in the hippocampus at early disease stages, which caused a decline of 5hmC levels and led young 2×Tg-AD mice to present with advanced stages of AD-related pathological hallmarks, including Aß accumulation, GFAP-positive astrogliosis and Iba1-positive microglia overgrowth as well as the overproduction of pro-inflammatory factors. Additionally, the loss of Tet2 in the 2×Tg-AD mice at 5 months of age accelerated hippocampal-dependent learning and memory impairments compared to age-matched control 2×Tg-AD mice. In contrast, restoring Tet2 expression in adult neural stem cells isolated from aged 2×Tg-AD mice hippocampi increased 5hmC levels and increased their regenerative capacity, suggesting that Tet2 might be an exciting target for rejuvenating the brain during aging and AD. Further, hippocampal RNA sequencing data revealed that the expression of altered genes identified in both Tet2 knockdown and control 2×Tg-AD mice was significantly associated with inflammation response. Finally, we demonstrated that Tet2-mediated 5hmC epigenetic modifications regulate AD pathology by interacting with HDAC1. These results suggest a combined approach for the regulation and treatment of AD-related memory impairment and cognitive symptoms by increasing Tet2 via HDAC1 suppression.

Relationship between growth hormone deficiency and nonalcoholic fatty liver disease in patients with pituitary stalk interruption syndrome.

BACKGROUND: Pituitary stalk interruption syndrome (PSIS), characterized by thinning or disappearance of the pituitary stalk, hypoplasia of the anterior pituitary, and an ectopic posterior pituitary, can lead to congenital combined pituitary hormone deficiency. There is a high prevalence of various metabolic disorders, including nonalcoholic fatty liver disease (NAFLD), in this population. OBJECTIVE: To investigate the characteristics of NAFLD in Chinese adult patients with PSIS and its association with growth hormone deficiency. DESIGN: Retrospective cross-sectional study in a tertiary referral center of China. PATIENTS: Adult patients with PSIS diagnosed, followed up between September 2019 and August 2021, were consecutively enrolled. MEASUREMENTS: Abdominal ultrasonography images were evaluated and noninvasive fibrosis scores were determined to assess the severity of NAFLD. Anthropometric, clinical, and biochemical parameters were compared between patients with and without NAFLD. Logistic regression was performed to assess the independent effects of insulin-like growth factor-1 (IGF-1) on NAFLD. RESULTS: A total of 93 patients (77 men, 16 women, mean age: 29.6 ± 7.1 years) were included. The prevalence of NAFLD and advanced fibrosis/cirrhosis was 50.5% and 4.3%, respectively. Insufficient hormone therapy and prominent metabolic disorders, including central obesity, dyslipidemia, insulin resistance, and metabolic syndrome, were more common in the NAFLD (+) group. After adjusting for multiple variables, IGF-1 <-2 standard deviation score (SDS) was found to be associated with an increased prevalence of NAFLD (odds ratio [OR]: 4.92, 95% confidence interval [CI]: 1.21-24.55, p = .035). Per 1 SDS increase in IGF-1 was associated with a 27% lower risk of NAFLD (OR: 0.73, 95% CI: 0.52-0.97, p = .042). CONCLUSION: NAFLD is a frequent comorbidity among Chinese adult patients with PSIS and is strongly associated with lower IGF-1 levels. Timely and appropriate hormone replacement, particularly growth hormone may contribute to decreasing the risk of NAFLD in these patients.

Long-term immune responses in patients with confirmed novel coronavirus disease-2019: a 9-month prospective cohort study in Shanghai, China.

BACKGROUND: The duration of antibodies against SARS-CoV-2 in Covid-19 patients remains uncertain. Longitudinal serological studies are needed to prevent disease and transmission of the virus. METHODS: In 2020, 414 blood samples were tested, obtained from 157 confirmed Covid-19 patients, in a prospective cohort study in Shanghai. RESULTS: The seropositive rate of IgM peaked at 40.5% (17/42) within 1 month after illness onset and then declined. The seropositive rate of IgG was 90.6% (58/64) after 2 months, remained above 85% from 2 to 9 months and was 90.9% (40/44) after 9 months. Generalized estimating equations models suggested that IgM (P < 0.001) but not IgG significantly decreased over time. Age ≥ 40 years (adjusted odds ratio [aOR] 4.531; 95% confidence interval [CI] 1.879-10.932), and cigarette smoking (aOR 0.344; 95% CI 0.124-0.951) were associated with IgG, and age ≥ 40 years (aOR 2.820; 95% CI 1.579-5.036) was associated with IgM. After seroconversion, over 90% and 75.1% of subjects were estimated to remain IgG-positive 220 and 254 days, respectively. Of 1420 self-reported symptoms questionnaires, only 5% reported symptoms 9 months after onset. CONCLUSIONS: In patients with a history of natural infection, anti-SARS-CoV-2 IgG is long-lived, being present for at least 9 months after illness onset. The long duration of natural immunity can mitigate and eliminate Covid-19 and the ongoing pandemic.

Bone Mineral Density in Pituitary Stalk Interruption Syndrome: The Role of Insulin-Like Growth Factor-1 and Testosterone at Different Skeletal Sites.

OBJECTIVE: This study aimed to determine the clinical indicators influencing bone mineral density (BMD) of the lumbar spine and femoral neck in patients with pituitary stalk interruption syndrome (PSIS) who underwent multiple hormone replacement therapy (MHRT). METHODS: Male patients with PSIS (n = 51) who underwent MHRT for at least 1 year were enrolled in this study. Their BMD parameters were recorded and compared with age-, weight-, and height-matched control adults. In addition, we performed multiple linear regression analysis to correlate clinical parameters with BMD parameters at 2 different sites. RESULTS: Fifty-one patients with PSIS had a mean age of 30.39 ± 5.50 years. After 36 months of treatment, patients with PSIS who underwent MHRT had slightly lower BMD than those in the control group. Multiple linear regression models revealed a positive association between the Z-score values for the lumbar spine with treatment duration (r = 0.453, P < .001), insulin-like growth factor-1 (IGF-1) standard deviation score (SDS) values (r = 0.248, P = .038), and total testosterone level (r = 0.260, P = .036) and a positive association between the Z-score values for the femoral neck with treatment duration (r = 0.425, P < .001) and IGF-1 SDS values (r = 0.338, P = .009). CONCLUSION: Collectively, long-term MHRT improves bone density in patients with PSIS to the normal range. A combination of recombinant human growth hormone replacement is more beneficial to the BMD than non-recombinant human growth hormone treatment. Moreover, serum IGF-1 contributes to femoral and lumbar mineralization, whereas serum testosterone plays a role in lumbar mineralization.

Efficacy of Pulsatile Gonadotropin-Releasing Hormone Therapy in Male Patients: Comparison between Pituitary Stalk Interruption Syndrome and Congenital Hypogonadotropic Hypogonadism.

OBJECTIVE: Pulsatile gonadotropin-releasing hormone (GnRH), widely used to induce spermatogenesis in congenital hypogonadotropic hypogonadism (CHH) patients, can restore the pituitary-testis axis function in men with pituitary stalk interruption syndrome (PSIS). This retrospective study aimed to compare the differences in the long-term efficacy of pulsatile GnRH therapy on PSIS and CHH. METHODS: Patients with PSIS (n = 25) or CHH (n = 64) who received pulsatile GnRH therapy for ≥3 months were included in this retrospective study. The rate of successful spermatogenesis, the median time to achieve spermatogenesis, serum gonadotropins, total testosterone, and testicular size were compared. RESULTS: Baseline characteristics were comparable except for the lower basal testosterone, triptorelin-stimulated peak luteinizing hormone (LH), and follicle-stimulating hormone in patients with PSIS. With similar duration of treatment and a significantly higher GnRH dose (P < .001), small increments in LH (2.82 [1.4, 4.55] vs 5.89 [3.88, 8.02] IU/L; P < .001), total testosterone (0.38 [0, 1.34] vs 2.34 [1.34, 3.66] ng/mL; P < .001), and testicular volume (5.3 ± 4.5 vs 8.8 ± 4.8 mL, P < .05) were observed. However, spermatogenesis rate (52.0% vs 70.3%, P > .05), median time of sperm appearance (14 vs 11 months, P > .05), sperm concentration, and progressive motility were comparable. Basal testicular volume (hazard ratio, 1.13; 95% CI, 1.01-1.27) and peak LH levels (hazard ratio, 1.11; 95% CI, 1.0-1.23) were predictors for early sperm appearance. CONCLUSIONS: Pulsatile GnRH therapy can improve gonad function and induce spermatogenesis in men with PSIS. However, its efficacy may be inferior to that in CHH.

Impaired blood-brain barrier in the microbiota-gut-brain axis: Potential role of bipolar susceptibility gene TRANK1.

Bipolar disorder (BD) is a common psychiatric illness with high prevalence and disease burden. Accumulating susceptibility genes for BD have been identified in recent years. However, the exact functions of these genes remain largely unknown. Despite its high heritability, gene and environment interaction is commonly accepted as the major contributing factor to BD pathogenesis. Intestine microbiota is increasingly recognized as a critical environmental factor for human health and diseases via the microbiota-gut-brain axis. BD individuals showed altered diversity and compositions in the commensal microbiota. In addition to pro-inflammatory factors, such as interleukin-6 and tumour necrosis factor-α, type 1 interferon signalling pathway is also modulated by specific intestinal bacterial strains. Disruption of the microbiota-gut-brain axis contributes to peripheral and central nervous system inflammation, which accounts for the BD aetiology. Administration of type 1 interferon can induce the expression of TRANK1, which is associated with elevated circulating biomarkers of the impaired blood-brain barrier in BD patients. In this review, we focus on the influence of intestine microbiota on the expression of bipolar gene TRANK1 and propose that intestine microbiota-dependent type 1 interferon signalling is sufficient to induce the over-expression of TRANK1, consequently causing the compromise of BBB integrity and facilitating the entrance of inflammatory mediators into the brain. Activated neuroinflammation eventually contributes to the occurrence and development of BD. This review provides a new perspective on how gut microbiota participate in the pathogenesis of BD. Future studies are needed to validate these assumptions and develop new treatment targets for BD.

IGF2 deficiency causes mitochondrial defects in skeletal muscle.

Exercise training improves muscle fitness in many aspects, including induction of mitochondrial biogenesis and maintenance of mitochondrial dynamics. The insulin-like growth factors were recently proposed as key regulators of myogenic factors to regulate muscle development. The present study aimed to investigate the physical exercise impact on insulin-like growth factor 2 (IGF2) and analyzed its functions on skeletal muscle cells in vitro. Using online databases, we stated that IGF2 was relatively highly expressed in skeletal muscle cells and increased after exercise training. Then, IGF2 deficiency in myotubes from C2C12 and primary skeletal muscle cells (PMSCs) led to impaired mitochondrial function, reduced mitochondria-related protein content, and decreased mitochondrial biogenesis. Furthermore, we explored the possible regulatory pathway and found that mitochondrial regulation in skeletal muscle cells might occur through IGF2-Sirtuin 1 (SIRT1)-peroxisome proliferator-activated receptor-γ co-activator-1α (PGC1α) signaling pathway. Therefore, the present study first demonstrated the relationship between IGF2 and mitochondria in skeletal muscle.

Knock-down of circular RNA H19 induces human adipose-derived stem cells adipogenic differentiation via a mechanism involving the polypyrimidine tract-binding protein 1.

PURPOSE: The metabolic syndrome (MetS) is characterized of a cluster of medical disorders. Altered function of adipose tissue has a significant impact on whole-body metabolism and represents a key driver for MetS. In this study, we aim to explore the function of human circular RNA H19 (hsa_circH19) in human adipose-derived stem cells (hADSCs). METHODS: The blood samples from MetS patients and normal subjects were used to determine the expression level of the hsa_circH19. After knock-down of hsa_circH19 in hADSCs, we measured the expression of adipogenic genes. Oil red O, Nile red staining assay and triglyceride assessment were performed to examine the role of hsa_circH19 in hADSCs differentiation. Then, RNA Pull-down and RIP assays were conducted to explore the related RNA binding protein of hsa_circH19. IF was performed to determine the potential molecular regulatory mechanism. RESULTS: After accounting for confounding factors, high levels of hsa_circH19 remained an independent risk factor for MetS. Furthermore, the knockdown of hsa_circH19 significantly increased the expression of adipogenic genes and the formation of lipid droplets. Bioinformatics analyses revealed that has_circH19 shared multiple binding sites with polypyrimidine tract-binding protein 1 (PTBP1) and their interaction was validated by circRNA pull-down and RIP assays. Mechanistically, depletion of hsa_circH19 triggered translocation of sterol-regulatory element binding proteins (SREBP1) from cytoplasm to nucleus in the presence of PTBP1. CONCLUSION: Our experiments suggest that knockdown of hsa_circH19 promotes hADCSs adipogenic differentiation via targeting of PTBP1. In consequence, the expression of hsa_circH19 might correlated to lipid metabolism in adipose tissue from MetS.

Applied anatomy of pelvic lymph nodes and its clinical significance for prostate cancer:a single-center cadaveric study.

BACKGROUND: Pelvic lymph node dissection (PLND) is one of the most important steps in radical prostatectomy (RP). Not only can PLND provide accurate clinical staging to guide treatment after prostatectomy but PLND can also improve the prognosis of patients by eradicating micro-metastases. However, reports of the number of pelvic lymph nodes have generally come from incomplete dissection during surgery, there is no anatomic study that assesses the number and variability of lymph nodes. Our objective is to assess the utility of adopting the lymph node count as a metric of surgical quality for the extent of lymph node dissection during RP for prostate cancer by conducting a dissection study of pelvic lymph nodes in adult male cadavers. METHODS: All 30 adult male cadavers underwent pelvic lymph node dissection (PLND), and the lymph nodes in each of the 9 dissection zones were enumerated and analyzed. RESULTS: A total of 1267 lymph nodes were obtained. The number of lymph nodes obtained by limited PLND was 4-22 (14.1 ± 4.5), the number obtained by standard PLND was 16-35 (25.9 ± 5.6), the number obtained by extended PLND was 17-44 (30.0 ± 7.0), and the number obtained by super-extended PLDN was 24-60 (42.2 ± 9.7). CONCLUSIONS: There are substantial inter-individual differences in the number of lymph nodes in the pelvic cavity. These results have demonstrated the rationality and feasibility of adopting lymph node count as a surrogate for evaluating the utility of PLND in radical prostatectomy, but these results need to be further explored.

LncRNAH19 improves insulin resistance in skeletal muscle by regulating heterogeneous nuclear ribonucleoprotein A1.

BACKGROUND: Skeletal muscle is essential for glucose and lipid metabolism. Growing evidence reveals the importance of long non-coding RNAs (LncRNAs) in metabolism. This study aimed to investigate the function of LncRNA H19 (H19) in lipid metabolism of skeletal muscle and its potential mechanisms. METHODS: Glucose tolerance, serum insulin and lipid content in serum and skeletal muscle were determined in control and H19-overexpressed db/db mice. Lipid metabolism was evaluated in H19-overexpressed or H19-silencing muscle cells by detecting lipid contents and mitochondria related functions. The underlying mechanisms were explored by RNA pull-down, mass spectrometry and RNA immunoprecipitation (RIP). RESULTS: H19 was downregulated in skeletal muscle of db/db mice. H19 overexpression in db/db mice inhibited lipid ectopic deposition in skeletal muscle, meanwhile improved glucose intolerance and insulin resistance as compared with control db/db mice treated with ad-GFP. Furthermore, overexpression of H19 reversed FFA-induced lipid accumulation and increased cellular respiration in muscle cells, while H19 knockdown exhibited opposite effects in muscle cells. Mechanistically, H19 interacted with heterogeneous nuclear ribonucleoprotein (hnRNPA1) which was validated by RNA pulldown and RIP analysis, which increased translation of fatty acid oxidation closely related genes PGC1a and CPT1b. CONCLUSION: Our data suggest that overexpression of H19 ameliorates insulin resistance by reducing ectopic lipid accumulation in skeletal muscle. The possible underlying mechanisms are that overexpression of lncRNAH19 promotes fatty acids oxidation via targeting of hnRNPA1. Video abstract.

Epidemiological and clinical characteristics of 161 discharged cases with coronavirus disease 2019 in Shanghai, China.

BACKGROUND: In December 2019, the outbreak of coronavirus disease 2019 (COVID-19) began in Wuhan, China, and rapidly spread to other regions. We aimed to further describe the epidemiological and clinical characteristics of discharged COVID-19 cases and evaluate the public health interventions. METHODS: We collected epidemiological and clinical data of all discharged COVID-19 cases as of 17 February 2020 in Shanghai. The key epidemiological distributions were estimated and outcomes were also compared between patients whose illness were before 24 January and those whose illness were after 24 January. RESULTS: Of 161 discharged COVID-19 cases, the median age was 45 years, and 80 (49.7%) cases were male. All of the cases were categorized as clinical moderate type. The most common initial symptoms were fever (85.7%), cough (41.0%), fatigue (19.3%), muscle ache (17.4%), sputum production (14.9%), and there were six asymptomatic cases. 39 (24.2%) cases got infected in Shanghai, and three of them were second-generation cases of Shanghai native cases. The estimated median of the time from onset to first medical visit, admission, disease confirmation, and discharge for 161 cases was 1.0 day (95% CI, 0.6-1.2), 2.0 days (95% CI, 1.5-2.6), 5.2 days (95% CI, 4.6-5.7), 18.1 days (95% CI, 17.4-18.8), respectively. The estimated median of the time from admission to discharge was 14.0 days (95% CI, 13.3-14.6). The time from onset to first medical visit, admission and disease confirmation were all shortened after the Shanghai's first-level public health emergency response. In Cox regression model, the significant independent covariates for the duration of hospitalization were age, the time from onset to admission and the first-level public health emergency response. CONCLUSIONS: Local transmission had occurred in Shanghai in late January 2020. The estimated median of the time from onset to discharge of moderate COVID-19 was 18.1 days in Shanghai. Time intervals from onset to first medical visit, admission and disease confirmation were all shortened after the Shanghai's first-level public health emergency response. Age, the first-level public health emergency response and the time from onset to admission were the impact factors for the duration of hospitalization.

Three infection clusters related with potential pre-symptomatic transmission of coronavirus disease (COVID-19), Shanghai, China, January to February 2020.

We report three clusters related with potential pre-symptomatic transmission of coronavirus disease (COVID-19) between January and February 2020 in Shanghai, China. Investigators interviewed suspected COVID-19 cases to collect epidemiological information, including demographic characteristics, illness onset, hospital visits, close contacts, activities' trajectories between 14 days before illness onset and isolation, and exposure histories. Respiratory specimens of suspected cases were collected and tested for SARS-CoV-2 by real-time reverse-transcriptase polymerase chain reaction (rRT-PCR) assay. The interval between the onset of illness in the primary case and the last contact of the secondary case with the primary case in our report was 1 to 7 days. In Cluster 1 (five cases), illness onset in the five secondary cases was 2 to 5 days after the last contact with the primary case. In Cluster 2 (five cases) and Cluster 3 (four cases), the illness onset in secondary cases occurred prior to or on the same day as the onset in the primary cases. The study provides empirical evidence for transmission of COVID-19 during the incubation period and indicates that pre-symptomatic person-to-person transmission can occur following sufficient exposure to confirmed COVID-19 cases. The potential pre-symptomatic person-to-person transmission puts forward higher requirements for prevention and control measures.

Benzene induces haematotoxicity by promoting deacetylation and autophagy.

Chronic exposure to benzene is known to be associated with haematotoxicity and the development of aplastic anaemia and leukaemia. However, the mechanism underlying benzene-induced haematotoxicity, especially at low concentrations of chronic benzene exposure has not been well-elucidated. Here, we found that increased autophagy and decreased acetylation occurred in bone marrow mononuclear cells (BMMNCs) isolated from patients with chronic benzene exposure. We further showed in vitro that benzene metabolite, hydroquinone (HQ) could directly induce autophagy without apoptosis in BMMNCs and CD34+ cells. This was mediated by reduction in acetylation of autophagy components through inhibiting the activity of acetyltransferase, p300. Furthermore, elevation of p300 expression by Momordica Antiviral Protein 30 Kd (MAP30) or chloroquine reduced HQ-induced autophagy. We further demonstrated that in vivo, MAP30 and chloroquine reversed benzene-induced autophagy and haematotoxicity in a mouse model. Taken together, these findings highlight increased autophagy as a novel mechanism for benzene-induced haematotoxicity and provide potential strategies to reverse this process for therapeutic benefits.

Thoughts of death affect reward learning by modulating salience network activity.

Thoughts of death substantially influence human behavior and psychological well-being. A large number of behavioral studies have shown evidence that asking individuals to think about death or mortality salience leads to significant changes of their behaviors. These findings support the well-known terror management theory to account for the psychological mechanisms of existential anxiety. However, despite increasing findings of mortality salience effects on human behavior, how the brain responds to reminders of mortality and changes the activity underlying subsequent behavior remains poorly understood. By scanning healthy adults (N = 80) of both sexes using functional magnetic resonance imaging, we showed that, relative to reading emotionally neutral sentences, reading sentences that evoke death-related thoughts decreased the salience network activity, reduced the connectivity between the cingulate cortex and other brain regions during a subsequent resting state, and dampened the speed of learning reward-related objects and cingulate responses to loss feedback during a subsequent reward learning task. In addition, the decreased resting-state cingulate connectivity mediated the association between salience network deactivations in response to reminders of mortality and suppressed cingulate responses to loss feedback. Finally, the suppressed cingulate responses to loss feedback further predicted the dampened speed of reward learning. Our findings demonstrate sequential modulations of the salience network activity by mortality salience, which provide a neural basis for understanding human behavior under mortality threat.

MicroRNA-149-5p regulates blood-brain barrier permeability after transient middle cerebral artery occlusion in rats by targeting S1PR2 of pericytes.

Blood-brain barrier (BBB) disruption caused by reperfusion injury after ischemic stroke is an intractable event conducive to further injury. Brain pericytes play a vital role in maintaining BBB integrity by interacting with other components of the BBB. In this study, we found that sphingosine-1-phosphate receptor (S1PR)2 expressed in pericytes was significantly up-regulated after ischemia in vivo and in vitro. By using a S1PR2 antagonist (JTE-013), we showed that S1PR2 plays a critical role in the induction of BBB permeability of transient middle cerebral artery occlusion (tMCAO) rats and the in vitro BBB model. Furthermore, we discovered that S1PR2 may decrease N-cadherin expression and increase pericyte migration via NF-κB p65 signal and found that S1PR2 could be regulated by miR-149-5p negatively, which was decreased in the ischemic boundary zone and cultured pericytes after ischemia. Overexpression of miR-149-5p in cultured pericytes substantially increased N-cadherin expression and decreased pericyte migration, which decreased BBB leakage in the in vitro model. Up-regulating miR-149-5p by intracerebroventricular injection of agomir-149-5p attenuated BBB permeability and improved the outcomes of tMCAO rats significantly. Thus, our data suggest that miR-149-5p may serve as a potential target for treatment of BBB disruption after ischemic stroke.-Wan, Y., Jin, H.-J., Zhu, Y.-Y., Fang, Z., Mao, L., He, Q., Xia, Y.-P., Li, M., Li, Y., Chen, X., Hu, B. MicroRNA-149-5p regulates blood-brain barrier permeability after transient middle cerebral artery occlusion in rats by targeting S1PR2 of pericytes.

MicroRNA-130a regulates cerebral ischemia-induced blood-brain barrier permeability by targeting Homeobox A5.

Blood-brain barrier (BBB) disruption plays a critical role in brain injury induced by cerebral ischemia, and preserving BBB integrity during ischemia could alleviate cerebral injury. We examined the role of miR-130a in ischemic BBB disruption by using models of rat middle cerebral artery occlusion and cell oxygen-glucose deprivation. We found that ischemia significantly increased microRNA-130a (miR-130a) level and that miR-130a was predominantly from brain microvascular endothelial cells. Antagomir-130a, an antagonist of miR-130a, could attenuate brain edema, lower BBB permeability, reduce infarct volume, and improve neurologic function. MiR-130a overexpression induced by miR-130a mimic increased monolayer permeability, and intercellular inhibition of miR-130a by a miR-130a inhibitor suppressed oxygen-glucose deprivation-induced increase in monolayer permeability. Moreover, dual luciferase reporter system showed that Homeobox A5 was the direct target of miR-130a. MiR-130a, by inhibiting Homeobox A5 expression, could down-regulate occludin, thereby increasing BBB permeability. Our results suggested that miR-130a might be implicated in ischemia-induced BBB dysfunction and serve as a target for the treatment of ischemic stroke.-Wang, Y., Wang, M.-D., Xia, Y.-P., Gao, Y., Zhu, Y.-Y., Chen, S.-C., Mao, L., He, Q.-W., Yue, Z.-Y., Hu, B. MicroRNA-130a regulates cerebral ischemia-induced blood-brain barrier permeability by targeting Homeobox A5.